Review

Pisa syndrome in Parkinson’s disease and parkinsonism:

clinical features, pathophysiology, and treatment
Paolo Barone, Gabriella Santangelo, Marianna Amboni, Maria Teresa Pellecchia, Carmine Vitale

Pisa syndrome is defined as a reversible lateral bending of the trunk with a tendency to lean to one side. It is a frequent Lancet Neurol 2016; 15: 1063–74
and often disabling complication of Parkinson’s disease, and has also been described in several atypical forms of Neurodegenerative Diseases
parkinsonism and in neurodegenerative and psychiatric disorders after drug exposure and surgical procedures. Centre, Department of
Medicine and Surgery,
Although no consistent diagnostic criteria for Pisa syndrome are available, most investigations have adopted an
University of Salerno, Salerno,
arbitrary cutoff of at least 10° of lateral flexion for the diagnosis of the syndrome. Pathophysiological mechanisms Italy (P Barone MD,
underlying Pisa syndrome have not been fully explained. One hypothesis emphasises central mechanisms, whereby M Amboni MD,
Pisa syndrome is thought to be caused by alterations in sensory–motor integration pathways; by contrast, a peripheral M T Pellecchia MD); Department
of Psychology, Second
hypothesis emphasises the role of anatomical changes in the musculoskeletal system. Furthermore, several drugs are University of Naples, Caserta,
reported to induce Pisa syndrome, including antiparkinsonian drugs. As Pisa syndrome might be reversible, clinicians Italy (G Santangelo PhD);
need to be able to recognise this condition early to enable prompt management. Nevertheless, further research is IDC-Hermitage-Capodimonte,
needed to determine optimum treatment strategies. Naples, Italy (G Santangelo,
M Amboni, C Vitale MD); and
Department of Motor Sciences
Introduction research, and explore the possible treatment options. and Wellness, University
Patients with Parkinson’s disease or atypical Because Pisa syndrome is a potentially reversible Parthenope, Naples, Italy
parkinsonism can present with abnormal postures that condition, early recognition and management is crucial (C Vitale)

cause substantial disability and can affect quality of life. to limit the development of structural deformities that Correspondence to:
Carmine Vitale, Department of
Pisa syndrome, defined as a lateral deviation of the spine can cause severe and irreversible mechanical constraints
Motor Sciences and Wellness,
with a corresponding tendency to lean to one side,1,2 is affecting respiration, mobility, and postural stability. University Parthenope, Napoli,
one of the most common postural deformities seen in Italy
these patients, and lateral flexion of the trunk has been Definition and epidemiology cavit69@hotmail.com

described as “the scoliosis of parkinsonism”.3,4 The term
Pisa syndrome was originally used to describe trunk
dystonia or pleurothotonus secondary to antipsychotic
treatment.5 Subsequently, the term was applied to
patients with dementia,6–18 parkinsonism,19–27 and other
neurodegenerative diseases28–32 or neurological disorders
including normal pressure hydrocephalus and subdural
haematoma33,34 who developed lateral trunk flexion
without exposure to antipsychotic drugs. Additionally,
Pisa syndrome has been reported as a primary idiopathic
disorder.35 More recently, Pisa syndrome has been
described in patients with Parkinson’s disease after
modification of dopaminergic treatment or as a
complication of surgical procedures for Parkinson’s
disease management, such as pallidotomy and deep
brain stimulation (DBS).36–47
Occurrence of postural deformities, in the sagittal or
coronal plane or both, have been increasingly recognised
as a common complication of Parkinson’s disease and
have been associated with disease progression and
treatment.1,2 Other common postural abnormities that
present in patients with Parkinson’s disease and atypical
forms of parkinsonism include camptocormia, antecollis,
retrocollis, and scoliosis (panel).1
In this Review, we focus on Pisa syndrome in the
context of both Parkinson’s disease and atypical
parkinsonism. We provide a detailed update on the
definition, epidemiology, and clinical presentation
of this postural deformity. We discuss the possible
pathophysiological mechanisms underlying Pisa
syndrome and emphasise areas in need of further
The clinical definition of Pisa syndrome is derived
mainly from studies of Parkinson’s disease rather than
atypical parkinsonism. Despite decades of research,
there is no consensus on the degree of lateral trunk
flexion needed to define Pisa syndrome in Parkinson’s
disease. In 2007, Bonanni and colleagues48 defined Pisa
syndrome as a lateral flexion of the trunk of more than
15° that increases during walking, is not present when
supine, and occurs in the absence of any mechanical
restriction to trunk movement, with continuous
electromyographic (EMG) activity in the lumbar
paraspinal muscles ipsilateral to the bending side. More
recently, in 2011, Doherty and colleagues1 defined Pisa
syndrome as a pronounced lateral flexion of greater than
10° while standing, which can be almost completely
reversed by passive mobilisation or supine positioning.
These authors further differentiate between mobile
deformity (Pisa syndrome) and fixed deformity (scoliosis),
the latter being diagnosed when there is concomitant
lateral trunk flexion and vertebral rotation with a Cobb
angle of 10° in the coronal plane.1,49 Accordingly,
radiological confirmation in standing and supine
positions is needed for differential diagnosis of Pisa
syndrome. The proposed diagnostic criteria of 10 or 15°
of lateral trunk flexion might lack sensitivity, as they
exclude all patients with flexion of less than 10 or 15°,
which could evolve into clinically detectable Pisa
syndrome. Nevertheless, by proposing the use of
electrophysiological assessment in the diagnosis of Pisa
syndrome, Bonanni and colleagues48 focused mainly on a
restricted subset of patients with dystonic features. To

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 Review
Panel: Definitions of postural deformities in Parkinson’s
disease and parkinsonism
Camptocormia
Severe flexion (more than 45°) of the thoracolumbar spine in
the sagittal plane during standing and walking, almost
completely resolving in the recumbent position.
Antecollis
Severe forward flexion (more than 45°) of the head in the
sagittal plane, partially overcome by voluntary movement
but unable to fully extend the neck against gravity. Rarely
seen in Parkinson’s disease, it is frequent in multiple system
atrophy.
Retrocollis
Abnormal posture of the neck that is held in extension in the
sagittal plane. Rare in Parkinson’s disease, it is typical of
progressive supranuclear palsy.
Scoliosis
Flexion (more than 10°, according to the Cobb method) of
the spine in the coronal plane not overcome by voluntary or
passive movement, combined with axial rotation of the
vertebrae confirmed by radiograph.
overcome such limitations, further validation of
diagnostic criteria should be investigated in the context
of longitudinal studies with larger study populations.
The absence of a consensus on diagnostic criteria
and definition for Pisa syndrome contributes to the
inconsistent prevalence rates among studies, ranging
from 1·9% to 91%.1,2,48,50–52 These discrepancies might also
be explained by the inclusion of scoliosis as well as Pisa
Syndrome and forms of parkinsonism other than
Parkinson’s disease in some studies, and by the small
sample size of most studies.1–3,5,25,50,51 Two large Italian
studies have assessed the prevalence of Pisa syndrome in
Parkinson’s disease.48,52 Bonanni and colleagues48 found a
1·9% prevalence rate in a population of 1400 patients
with Parkinson’s disease and parkinsonism when using
a lateral trunk flexion criteria of 15°. In a multicentre
cross-sectional study of 1631 consecutive patients with
Parkinson’s disease, Tinazzi and colleagues52 reported a
prevalence of Pisa syndrome of 8·8% using the 10° lateral
flexion criteria. Conversely, Cervantes and colleagues53
found no cases of Pisa syndrome or antecollis in a cohort
of 416 consecutive patients with Parkinson’s disease
assessed for musculoskeletal deformities with the clinical
criteria proposed by Doherty and colleagues1 (ie, lateral
trunk flexion ≥10° for Pisa syndrome and neck forward
flexion ≥45° for antecollis). The absence of Pisa syndrome
was interpreted by the authors as the result of milder
disease stages in their Parkinson’s disease cohort.53
Pisa syndrome can occur in patients affected by atypical
forms of parkinsonism, especially multiple system
atrophy (MSA). The first description of probable Pisa
syndrome in a case of pathologically proven striatonigral
1064
degeneration—a feature of MSA—was reported in 1978
by Kan,20 who described a 64-year-old patient who
developed “a lumbar scoliosis resulting from muscular
dystonia” 2 years after onset of motor symptoms.20 Two
decades later, Colosimo and colleagues21 reported a
second case of Pisa syndrome, with sudden onset,
alongside a clinical diagnosis of probable MSA. Postural
abnormalities, including severe antecollis and Pisa
syndrome, are now recognised as potential indicators of
MSA. In a multicentre study from the European MSA
Study Group,24 Pisa syndrome was found in 42% of
57 patients with MSA with a predominant parkinsonian
phenotype (both probable and possible according to the
first consensus criteria) compared with 2·5% of
116 patients with Parkinson’s disease matched for age,
sex, and disease duration, reaching a specificity of 97·5%
in the differential diagnosis of these disorders.24 However,
the study lacks post-mortem confirmation of MSA or
Parkinson’s disease diagnosis, and the clinical diagnosis
of MSA was the gold standard used to assess the validity
of antecollis and Pisa syndrome as warning signs for this
disease.
Present evidence suggests that Pisa syndrome is a rare
feature of progressive supranuclear palsy (PSP). In a
series of 202 consecutive patients with Parkinson’s
disease, MSA, and PSP assessed for the presence of joint
and skeletal deformities, Ashour and colleagues25 reported
camptocormia in 5·3% of patients with PSP compared
with 12·2% of patients with Parkinson’s disease and
26·3% of patients with MSA, and scoliosis was described
in 5·3% of patients with PSP compared with 8·5% of
patients with Parkinson’s disease and 10·5% of patients
with MSA. Ashour and colleagues found no cases of Pisa
syndrome in their patient series, although this might be
due to the absence of validated diagnostic criteria and the
retrospective design of the study. Solla and colleagues26
described a 69-year-old patient with a diagnosis of
probable PSP who presented with a tonic flexion of the
trunk of at least 10° to the right that occurred 3 years after
the onset of motor symptoms. Furthermore, Noda and
colleagues27 have reported a case of probable PSP with
lateral flexion of the trunk, which worsened when the
patient was sitting (in a wheelchair) but was alleviated in
the supine position.
Clinical features and concomitant medical
conditions
Pisa syndrome can develop chronically with subtle onset
and gradual progression, or with an acute onset followed
by rapid worsening over months.1,51,52,54 The pattern of
onset has been classified according to the time taken to
develop clinically definite Pisa syndrome: acute
(<1 month), subchronic (≥1 month to <3 months), and
chronic (≥3 months). Using these definitions, Tinazzi
and colleagues52 found that most patients in their cohort
developed Pisa syndrome chronically. In chronic forms
of Pisa syndrome, a slight reversible tilting behaviour
www.thelancet.com/neurology Vol 15 September 2016

might occur when the patient is sitting or walking, which
precedes the later occurrence of clinically definite Pisa
syndrome; patients often do not perceive themselves as
leaning to one side.1,51,52,54 In such cases, progression of
the syndrome is slow, and causal factors might be
difficult to detect. Although acute onset is more likely to
be associated with drug exposure according to anecdotal
reports, there are no available data for the frequency of
Pisa syndrome onset after initiation of treatment with
dopaminergic drugs. In the only study that has
systematically explored the prevalence of drug-induced
Pisa syndrome, only 15% of patients with Parkinson’s
disease developed Pisa syndrome after changes to their
drug regimen, whereas no correlation with drug exposure
or treatment modification was noted in the remaining
85% of cases, regardless of whether the onset of the
syndrome was acute, subchronic, or chronic.52 This
absence of correlation might have been due to the cross-
sectional design of this study, which did not allow
accurate definition of the temporal relationship between
change in pharmacological regimen and Pisa syndrome
onset.
Drug-induced Pisa syndrome in Parkinson’s disease
can arise from an increase or decrease in the dose of
dopaminergic drugs, or might be due to insufficient dose
of antiparkinsonian treatments. In this regard, almost all
dopaminergic drugs, including levodopa, monoamine
oxidase inhibitors (MAO-I), catechol-O-methyltransferase
(COMT) inhibitors, and dopamine agonists, have been
associated with Pisa syndrome occurrence, with no clear
association between drug type and pattern of clinical
onset.36–43 Tinazzi and colleagues52 have also reported that
patients with Pisa syndrome in their cohort received
higher doses of daily levodopa than patients without Pisa
syndrome, and were more likely to be treated with a
combination of levodopa and dopamine agonists;
however, longitudinal studies are needed to confirm this
association. Acute Pisa syndrome with a close temporal
relation to drug exposure and transient relief after a
sensory trick to overcome abnormal posture (eg, any
motor act able to transiently improve posture alteration
not due to a mechanical effect) has been reported in
patients with Parkinson’s disease associated with a
dystonic-like cause (possible dystonic etiology of Pisa
syndrome in some Parkinson’s disease patients).1,50–52,55
Although most patients with Parkinson’s disease and
Pisa syndrome have been reported to lean towards the
side of their body that is less affected by Parkinson’s
disease, a 2015 study52 reported no difference in bending
between ipsilateral and contralateral sides, and others
have reported lateral flexion even in the absence of clear
asymmetry of parkinsonian signs.1,50 Finally, a recurrent
and alternating leaning behaviour towards both sides (ie,
metronome sign) has also been reported in patients with
Parkinson’s disease and Pisa syndrome.52,56
Patients with Pisa syndrome are usually older, have a
substantially longer disease duration, more severe
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Review
disease by Hoehn and Yahr scale (H&Y) staging, and
worse quality of life compared with patients without Pisa
syndrome.52 Vitale and colleagues57 reported a significant
association of Pisa syndrome with altered attention and
visuoperceptual dysfunction in patients with Parkinson’s
disease. Co-occurrence of other medical conditions such
as osteoporosis and arthrosis with lower body mass index
might increase the risk of developing Pisa syndrome,
whereas female gender decreases the risk of having
severe Pisa syndrome.2,52 Moderate-to-severe lower back
pain is sometimes reported by patients with Pisa
syndrome irrespective of the severity of lateral trunk
flexion and clinical onset.48,52 Finally, falls and veering gait
(ie, the progressive deviation of 30° or more towards one
side in three consecutive trials of 5 m walking distance)
are more likely to occur in patients with Parkinson’s
disease and Pisa syndrome than in patients with
Parkinson’s disease who do not have Pisa syndrome.52
Pisa syndrome can occur concomitantly with other
postural abnormalities. In some patients with Parkinson’s
disease, forward trunk flexion is associated with the
development of Pisa syndrome, especially in the advanced
stages of Parkinson’s disease.48,49,51 Co-occurrence of
postural deformities has been investigated with
conflicting results. Bonanni and colleagues48 found that
2·6% of patients in their cohort had Pisa syndrome in
association with anterior axial flexion, the classic feature
of camptocormia (forward trunk flexion greater than 45°).
The co-occurrence of a lateral flexion of greater than 10°
and a forward flexion of greater than 45° would probably
lead to more severe mechanical constraints and disability
(figure 1). Conversely, Tinazzi and colleagues52 did not
report any patients who fulfilled the diagnostic criteria for
camptocormia or other rarer postural disorders such as
antecollis (forward neck flexion greater than 45°) and
retrocollis associated with Pisa syndrome. These
discrepancies might be due in part to the sample sizes of
the studies, which were not statistically powered to detect
associations between postural abnormalities, and by the
recruitment of patients from outpatient clinics.
As parkinsonism progresses and postural deformities
become increasingly severe, pathological changes in the
soft tissues might promote the transition from a
reversible syndrome to a more permanent syndrome, in
turn leading to dyspnoea, exacerbation of pain, and
balance difficulties (table 1).1,49–52
Pathogenesis
The role of dopamine
The mechanisms underlying Pisa syndrome are probably
multifactorial and might differ according to the associated
disease. In non-parkinsonian patients, subacute onset of
Pisa syndrome has been associated with exposure to or
dose changes in both typical and atypical antipsychotics,58–92
other psychotropic drugs including mood stabilisers,
antidepressants, cholinesterase inhibitors,6–18,93–96 and even
antiemetics.97,98 Most of these studies were reports of
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 Review
A B
C D
Dx
Figure 1: Clinical appearance of a patient with Parkinson’s disease and Pisa syndrome
(A and B) 69-year-old female patient with Parkinson’s disease and Pisa syndrome with forward flexion of the trunk
(mixed deformity), with a predominantly coronal plane deformity. (C) Anteroposterior radiograph of the same
patient standing, showing right leaning of the trunk. Note that the spinous processes are aligned without rotation
of vertebral bodies, thus differentiating Pisa syndrome from scoliosis. The lines provide a goniometric reference.
(D) Supine projection showing a complete resolution of Pisa syndrome while lying down. Dx=patient’s right side.
anecdotal cases with no discussion of associated
drug-induced parkinsonism. In parkinsonian patients,
Pisa syndrome has been associated with the initiation or
change in dose of dopamine agonists,36,39,41 variation in
1066
levodopa regimen,38,39 and addition of rasagiline and
COMT inhibitors to levodopa treatment.40,42,43,99
Accordingly, it has been hypothesised that a cholinergic–
dopaminergic imbalance is involved in the development
of drug-induced Pisa syndrome.11 Dopamine-replacement
therapy might promote development of Pisa syndrome in
predisposed patients by priming the basal ganglia
circuitry. Priming is a pharmacological occurrence after
denervation of the nigrostriatal pathway (such as in
Parkinson’s disease) associated with sensitisation of
dopaminergic receptors.100 However, axial symptoms in
Parkinson’s disease respond poorly to dopaminergic
treatment, suggesting that dysregulation of other
neurotransmitter systems might have a role in the
development of lateral trunk flexion. Apart from
neurotransmitter dysfunction, Pisa syndrome might be
explained by dysfunction of postural control systems that
maintain balance and orientation in response to both
internal and external perturbation and require a complex
interaction between motor, sensory, and cognitive
systems (figure 2).101–103
The role of the basal ganglia
Motor dysfunction, including bradykinesia, rigidity,
and postural instability, are integral characteristics of
parkinsonism, and the associated body asymmetry
might predispose patients to lateral trunk flexion.
The basal ganglia seem to have a primary role in the
pathogenesis of Pisa syndrome, as suggested by
the observation of lateral trunk flexion contralateral to
the side of unilateral stereotactic subthalamotomy or
pallidotomy.44–46 Nevertheless, as noted above, in patients
with Pisa syndrome, there is no clear laterality as
they can either lean towards or away from the side
most affected by Parkinson’s disease, suggesting the
contribution of factors other than basal ganglia
asymmetry in Pisa syndrome development. Furthermore,
Dx no pathological evidence of asymmetry was found in the
only reported autopsy of a patient with Pisa syndrome
and Parkinson’s disease.104 In MSA, a marked asymmetry
of striatal degeneration, as a proposed cause of Pisa
syndrome, has been suggested by asymmetry in
hypoperfusion on SPECT imaging, a slit-like
hyperintensity at the outer margin of one putamen on
MRI imaging and putaminal neuronal loss and
astrogliosis at autopsy.22 However, as these observations
were made in only one case of MSA, confirmation in
future studies is needed.
The role of sensorimotor dysfunction
The dysfunction of sensory and somatosensory systems
(ie, visual and vestibular systems) and its contribution to
postural control has previously been investigated in
patients with Parkinson’s disease without Pisa syndrome
with inconclusive results.105–111 Patients with Parkinson’s
disease are unable to properly control their postural
orientation based on sensory information from the
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 Review

muscles and joints, suggesting that a deficit in

proprioceptive information processing might contribute ≥15° lateral flexion of the trunk48 ≥10° lateral flexion of the trunk52
to poor signal integration in posture control.50,51,111 Participants Mean (SD) or % Participants Mean (SD) or %
Furthermore, patients with Parkinson’s disease and Pisa
Prevalence 26/1400* 1·9% 143/1631† 8·8%
syndrome have more difficulty in achieving good postural
Age (years) 9 72 (5·7) 143 71·1 (8·0)
alignment with gravity and have a greater velocity of body
sway than patients without Pisa syndrome.112 There is Sex
evidence to suggest a link between vestibular dysfunction Men 5/9 56% 79/143 55%
and lateral trunk flexion.100,113 Mamo and colleagues113 Women 4/9 44% 64/143 45%
reported vestibular dysfunction in patients with Disease duration (years) 9 10·3 (7·2) 143 9·6 (5·3)
Parkinson’s disease who developed transient contralateral UPDRS-III score 9 21 (5) 143 27·9 (10·4)
trunk flexion after unilateral thalamotomy and Hoehn & Yahr score 9 2·5 (0·5) 143 2·6 (0·8)
subthalamotomy. These investigators concluded that Pisa syndrome degrees 9 30 (7·2) 143 17 (7·4)
vestibular dysfunction, although necessary, was not MMSE score 9 21 (3·3) ·· ··
sufficient to induce postural abnormalities. Levodopa equivalent dose (mg) 9 858 (58·2) 143 570·4 (272·6)
Peripheral unilateral vestibular hypofunction, ipsilateral Latency of Pisa syndrome after ·· ·· 141 7 (5)
to the leaning side and contralateral to the side most onset of Parkinson’s disease (years)
affected by Parkinson’s disease, has recently been Pisa syndrome duration (years) 9 2·4 (0·9) 143 2·6 (2·5)
described in a small series of patients with Parkinson’s Pisa syndrome direction
disease and Pisa syndrome, and might contribute to the Right 4/9 44% 99/143 69%
patients’ postural abnormalities. Subclinical vestibular Left 5/9 56% 44/143 31%
hypofunction might also occur before the onset of Pisa Side of Parkinson’s disease symptoms at onset and Pisa syndrome inclination
syndrome in patients with Parkinson’s disease without Ipsilateral ·· ·· 58/143 41%
lateral trunk flexion.100 It is possible that as the disease Contralateral ·· ·· 59/143 41%
progresses and vestibular deficits increase alongside the Bilateral ·· ·· 26/143 18%
development of proprioceptive impairments, an adaptive Pisa syndrome pattern of onset
reweighting of sensory inputs occurs, leading to the <1 month (acute) ·· ·· 19/143 13%
lateral trunk flexion observed in patients with Parkinson’s ≥1 month to <3 months ·· ·· 24/143 17%
disease and Pisa syndrome. Although these findings (subchronic)
suggest a link between sensorimotor integration failure ≥3 months (chronic) ·· ·· 100/143 70%
and postural abnormalities, the role of proprioceptive Pisa syndrome development after drug modification
and vestibular dysfunctions and their contribution to Yes ·· ·· 21/143 15%
Pisa syndrome pathogenesis needs to be further validated No ·· ·· 122/143 85%
in the context of larger study populations. Pisa Syndrome awareness
Yes ·· ·· 119/143 83%
The role of body schema perception and cognition No ·· ·· 24/143 17%
Alterations in the perception of postural alignment and Back pain
abnormalities in subjective visual perception of verticality Yes 9/9 100% 101/143 71%
have also been reported in patients with Parkinson’s No 0/9 0% 42/143 29%
disease and Pisa syndrome, and might contribute to VAS pain score 9 71·8 (5·7)‡ 101/143 6 (2·3)§
postural deformity.1,50,52–54,114,115 Whether these alterations Metronome Pisa syndrome
are the result of defective integration of somatosensory Yes ·· ·· 13/134 10%
and vestibular input or secondary to abnormal spatial No ·· ·· 121/134 90%
cognition and body schema needs to be further Head compensation
investigated. Postural control requires complex motor– Yes ·· ·· 59/138 43%
cognitive interactions that rely on high attentional No ·· ·· 79/138 57%
resources and preserved executive functions;101–103 Compensatory effect of a sensory trick
however, until now, few studies have investigated the Yes ·· ·· 24/143 17%
association between cognitive deficits and postural No ·· ·· 119/143 83%
deformities in patients with Parkinson’s disease. In a Electromyographic recordings 26/26 100% ·· ··
small sample of patients with Parkinson’s disease,
impaired executive function, assessed with the Montreal UPDRS=Unified Parkinson’s Disease Rating Scale. MMSE=Mini mental State Examination. VAS=Visual Analogue Scale.
*In this study of 1400 patients with parkinsonism, 4726 had Pisa syndrome and underwent EMG assessment; nine were
Cognitive Assessment and the Frontal Assessment further admitted to botulin toxin versus placebo treatment. †In this study of 1631 patients with Parkinson’s disease,51
Battery, was recorded in those with Pisa syndrome 143 had Pisa syndrome, all of whom were selected for further assessment. ‡VAS interval 0–100. §VAS interval 1–10.
compared with those without Pisa syndrome.49 A 2015
Table 1: Clinical and demographic features of patients with Parkinson’s disease and Pisa syndrome
study57 investigated cognitive function in patients with
according to diagnostic criteria of ≥15° and ≥10° lateral trunk flexion, respectively
Parkinson’s disease with and without Pisa syndrome

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 Review

who did not differ on demographic features (ie, age at

Parkinson’s disease onset and disease duration) but did
have differences in motor disability and levodopa-
A equivalent daily dose. After controlling for motor
Cortex Cortex
disability and levodopa dose, patients with Pisa syndrome
scored significantly lower on specific tasks exploring
executive functions (ie, divided attention, inhibitory
Basal ganglia Basal ganglia control, and delayed free recall in verbal learning) and
perceptual visuospatial functions than patients with
Parkinson’s disease without postural deformities.57
Vestibular Brainstem Brainstem Vestibular
Because Pisa syndrome has been reported in more severe
cases of Parkinson’s disease, it is possible that as the
disease progresses, cognitive dysfunction becomes more
Visual
Visu
uall Visual severe, which in turn contributes to development of Pisa
syndrome.

The role of the trunk muscles

Proprioceptive
iocceptive Proprioceptive
Pisa syndrome has been interpreted by some
investigators as a dystonic posture on the basis of both
EMG findings (showing a tonic activation either in
paraspinal muscles or in the abdominal oblique muscles
ipsilateral to the side affected by deviation) and reports
Trunk muscles Trunk muscles
of improvement after administration of botulinum toxin
type A to the paraspinal muscles.48,116 However, the
dystonic posture hypothesis has been criticised because
B of the absence of clinical characteristics of dystonia,
Cortex Cortex such as overflow, twisting, and compensatory effects of
sensory tricks in patients with Pisa syndrome.52
Furthermore, two studies by the same group of
Basal ganglia Basal ganglia investigators, using the same diagnostic criteria for Pisa
syndrome, reported contradictory EMG patterns—
hyperactivity of paraspinal muscles ipsilateral to the
Vestibular Brainstem Brainstem Vestibular leaning side versus continuous activity contralateral to
the leaning side—thus only partially confirming the
dystonic theory.117,118 The differences in EMG findings
Visual Visual
between these two studies might be explained by the
EMG testing paradigms used (static vs dynamic or
standing vs sitting) and the limited number of muscles
assessed. Tinazzi and colleagues117,118 extended their
Proprioceptive Proprioceptive EMG study to more muscles in both static and dynamic
conditions (eg, paraspinal lumbar, paraspinal thoracic,
abdominal oblique, iliopsoas, and rectus femoris) and
found two different EMG patterns.118 The first pattern
was characterised by hyperactivity of lumbar paraspinal
Trunk muscles Trunk muscles muscles contralateral to the leaning side; half of the
patients with Parkinson’s disease also showed ipsilateral
Figure 2: Central control mechanisms of postural stability
hyperactivity of thoracic paraspinal muscles. The
(A) Normal conditions. (B) Parkinson’s disease. Postural control in healthy
individuals relies on network interactions of the cortex, basal ganglia, and second pattern, thoracic paraspinal hyperactivity, was
brainstem, which integrate motor (trunk muscles), sensory (visual, vestibular, contralateral in all patients. The investigators also
and proprioceptive), and cognitive systems. In a patient with Parkinson’s disease found hyperactivity of non-paraspinal muscles in both
and Pisa syndrome, asymmetrical basal ganglia functioning together with
impaired processing of sensory information (visual, vestibular, and
ipsilateral and contralateral sides, and concluded that
proprioceptive), cognitive dysfunctions, and altered perception of body hyperactivity of contralateral paraspinal muscles
alignment (cortex) might lead to asymmetric trunk muscle stimulation. Green probably compensates for the trunk leaning.118
and red lines indicate input and output pathways, respectively. Shaded areas and Although a primitive myopathy has been suggested to
lines indicate alterations of brain structures and pathways, respectively. Such
alterations might be due to the Parkinson’s disease pathology (brainstem, basal
explain Pisa syndrome,116 no pathological study exists to
ganglia, and cortex) or to concomitant medical conditions (vestibular or prove this hypothesis. In a study involving CT scans of
proprioceptive dysfunctions) paraspinal muscles, Tassorelli and colleagues found

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muscular atrophy that was more pronounced on the
leaning side, with a cranio-caudal gradient involving the
multifidus and latissimus dorsi muscles.116 An MRI study
has confirmed the presence of atrophy of the lumbar
paraspinal muscles with fatty degeneration that is
greater, and more prevalent, on the leaning side.118 Such
muscular atrophy might be explained as the consequence
of chronically altered posture rather than as a causative
factor, but further investigation is needed to understand
the role of muscular atrophy.
Management of Pisa syndrome
The management of Pisa syndrome represents a clinical
challenge mainly owing to the absence of high-quality,
specifically designed studies addressing this syndrome.
On the basis of the available data, Parkinson’s disease
drug revision and adjustment can be considered as
the first-line intervention, and pharmacological,
non-pharmacological, and surgical strategies as
second-line interventions. Owing to the lack of evidence
for the management of Pisa syndrome in atypical forms
of parkinsonism, we specifically focus on Pisa syndrome
treatment in idiopathic Parkinson’s disease. However, it
should be noted that the literature remains inconclusive
and definitive recommendations for treatment strategies
cannot be made (table 2).
Revision of drug regimen
When considering treatment options for Pisa syndrome,
the first step is to characterise its onset and progression
(acute, subchronic, or chronic) in relation to the
patient’s antiparkinsonian treatment regimen. In
particular, Pisa syndrome has been associated with
initiation and dose changes of dopamine agonists,36,39,41
levodopa,38,39 and addition of MAO and COMT
inhibitors.40,42,43,99 A close temporal relation between Pisa
syndrome occurrence and dopaminergic therapy
modification might enable early recognition of the
offending drug and its prompt withdrawal or dose
adjustment as a first-line treatment option.
Improvement of Pisa syndrome has been reported after
discontinuation or reduction of antiparkinsonian drugs
that had been initiated before the onset of Pisa
syndrome.36,38–43,99 Data are not available on the risk
associated with developing Pisa syndrome for specific
antiparkinsonian drugs, so it is not possible to speculate
about drug-specific mechanisms. However, Pisa
syndrome has been observed during off periods (ie,
worsening of parkinsonian symptoms when treatment
is less effective) in two patients with Parkinson’s
disease and motor fluctuations, which improved after
an increase of levodopa dose.38 In these cases, lateral
trunk flexion might have resembled end-of-dose
deterioration or off-period dystonia, suggesting that
Pisa syndrome could be associated with striatal
dopamine deficiency or an imbalance in the
dopaminergic–cholinergic systems.
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Review
Pharmacological treatment
In patients with Parkinson’s disease, according to the
assumption that Pisa syndrome could be due to
paraspinal muscles dystonia, treatment with botulinum
toxin has been used, although results have been
inconclusive. Bonanni and colleagues48 did a randomised,
double-blind, crossover, placebo-controlled trial in a
small cohort of patients with Parkinson’s disease and
Pisa syndrome; they found that injection of botulinum
toxin A into paraspinal muscles on the side of the trunk
flexion resulted in an improvement of the lateral bending
by 50–87·5% in six of nine patients.48 However, the
reason why some patients benefit from this treatment
and other do not is unexplained. More recently, the
injection of botulinum toxin A into the hyperactive trunk
muscles has been found to improve the effectiveness of
rehabilitation in a series of patients with Parkinson’s
disease and Pisa syndrome in a small, randomised,
placebo-controlled trial.119 Consistent with this, Dupeyron
and colleagues120 reported complete resolution of
abnormal posture after botulinum toxin A injection into
hyperactive quadratus lumborum muscles on the leaning
side in a patient with Parkinson’s disease. There have not
yet been any clinical trials assessing pharmacological
treatment approaches for pain in Pisa syndrome.
Non-pharmacological treatment
Only two small studies have assessed the effectiveness of
non-pharmacological treatment—ie, rehabilitation—for
Pisa syndrome in Parkinson’s disease. Findings have
been inconsistent and further studies assessing the
long-term effects are warranted. The first study was an
open trial including a group of 22 patients with
Parkinson’s disease with lateral trunk flexion (ranging
from mild to severe) and a control group of 22 patients
with Parkinson’s disease without lateral trunk flexion,
matched for age, disease duration, and severity.
The intervention consisted of a 4-week rehabilitation
programme specifically aimed at reducing rigidity and
improving flexibility and mobility of the trunk. The
investigators reported significant reduction of lateral
trunk flexion, which was maintained at 6 months after
the end of the rehabilitation programme.121 Capecci and
colleagues122 did a single-blind, randomised controlled
trial in which they assessed the efficacy of a 4-week
patient-tailored programme consisting of proprioceptive
and tactile stimulation combined with stretching and
postural re-education in 13 patients with Parkinson’s
disease and postural abnormalities of the trunk. Six of
13 treated patients also received kinesio taping of the
trunk muscles as additional treatment. The investigators
reported that at the end of the programme, the treated
patients had substantial but not lasting improvement of
the lateral bending. Furthermore, there was no difference
between patients who received combined rehabilitation
and kinesio taping and patients who received
rehabilitation only.123
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 Review
Surgical treatment
Few studies have specifically assessed the effects of DBS
on lateral trunk flexion. The available studies are mainly
case series or case reports and the results have been
inconclusive. In a retrospective study47 of ten patients
with Parkinson’s disease who had symptoms of Pisa
syndrome during on periods (ie, when parkinsonian
symptoms were adequately controlled with anti-
parkinsonian drugs), efficacy of subthalamic DBS in
reducing postural abnormalities was assessed. The
investigators reported substantial improvement in the
posture of patients who had mild-to-moderate Pisa
syndrome, but less consistent results in patients with
severe lateral trunk flexion, including no improvement
in some. Two studies124,125 have reported a beneficial effect
of DBS of the pedunculopontine nucleus in patients
with Pisa syndrome. However, this benefit was observed
only at a 6-month follow-up assessment and was not
maintained over time.125 On the basis of the few available
studies, it is not possible to determine whether DBS has
a direct effect on Pisa syndrome or whether any positive
effects associated with DBS might be attributed to post-
surgical modifications to the dopaminergic drug
regimen. Aside from its inconclusive role in the
management of Pisa syndrome, Parkinson’s disease
surgery has been suggested to be responsible for Pisa
syndrome in some cases; a long-term follow-up study
has shown that patients with Parkinson’s disease treated
with either unilateral subthalamotomy44 or pallidotomy45,46
occasionally develop postural abnormalities.
Finally, spinal realignment surgery might be required
in severe cases of Pisa syndrome associated with
compression fracture, osteonecrosis, and intractable
radicular and back pain. Spinal surgery in patients
Action
First-line approach Accurate review of introduction or modification of
antiparkinsonian drugs to adjust or discontinue the possible
inducing drugs36,39–43,99,113
Second-line approach
Pharmacological Botulinum toxin A in hyperactive paraspinal muscles48,118,119
treatment
Non- Rehabilitation programmes specifically aimed at reducing
pharmacological rigidity and improving flexibility and mobility of the trunk120
treatment Patient-tailored proprioceptive and tactile stimulation,
combined with stretching and postural re-education121
Surgical Subthalamic deep brain stimulation47 Pedunculopontine deep Few data are available: data suggest subthalamic deep brain C
treatment brain stimulation122,123 Spinal realignment surgery124
* Level A=recommendation based on consistent and good-quality patient-oriented evidence (randomised double-blind controlled trials of sufficient size and consistency).
Level B=recommendation based on inconsistent or limited-quality patient-oriented evidence (randomised clinical trials of insufficient size or other comparative trials).
Level C=recommendation based on consensus, usual practice, opinion, disease-oriented evidence, or case series.
Table 2: Treatment options for the management of Pisa syndrome in Parkinson’s disease
1070
with Parkinson’s disease is challenging owing to
commonly occurring complications—namely construct
or fusion-related complications, infection, and a
frequent need for revision surgery, mainly for
progressive kyphosis or spine segmental instability. In
particular, postoperative sagittal imbalance would
represent one of the main factors responsible for
construct failure and the need for revision surgery. Risk
factors for surgical complications include advanced
Parkinson’s disease, severe disability, and poor
functional status.124 A 2015 review of case series suggests
that a favourable outcome depends on appropriate
selection of surgical patients on the basis of an
interdisciplinary approach involving both surgeons and
movement disorders specialists.126
Conclusions and future directions
Pisa syndrome in Parkinson’s disease could be the
result of multiple factors including asymmetric basal
ganglia function, impaired processing of sensory
information, cognitive dysfunction, and altered
perception of body alignment. Co-occurrence of
concomitant medical conditions such as osteoporosis
and arthrosis might further increase the risk of
developing postural abnormalities and promote the
transition from a reversible syndrome to a chronic
condition with irreversible structural deformities
(structured Pisa syndrome). Overlap between complex
central (dopaminergic and non-dopaminergic) and
peripheral mechanisms could explain the clinical
heterogeneity and prognosis of Pisa syndrome in
Parkinson’s disease and other forms of parkinsonism,
but more research is needed to better define this
syndrome and to optimise its management.
Commentary on action Level of
evidence*
Antiparkinsonian drug changes or discontinuation could C
worsen Pisa syndrome
Effectiveness of botulinum toxin A injections is inconsistent B
between patients
Few data are available; trials of rehabilitation programmes B and C
have been done in small cohorts and data on long-term
effects are inconsistent
stimulation might be effective in mild or moderate Pisa
syndrome; pedunculopontine deep brain stimulation could
be beneficial but its effects are not lasting; owing to the
high risk of complications, spinal surgery should be reserved
for selected cases associated with compression fracture,
osteonecrosis, and intractable pain
www.thelancet.com/neurology Vol 15 September 2016

Consensus on diagnostic criteria are needed for Pisa
syndrome, which should include goniometric and
radiological measures. The current absence of both
validated diagnostic criteria and longitudinal studies
prevent us from determining the timing of Pisa syndrome
onset and defining the risk factors, including drug
exposure or specific parkinsonian clinical features, which
might predispose patients to development of this
syndrome. The common clinical observation of a
reversible and unconscious tilting behaviour (less than
10°) in some patients with Parkinson’s disease raises the
question of whether these patients are at risk of developing
structured Pisa syndrome. Early detection of lateral trunk
flexion, irrespective of its goniometric values, would be
relevant in preventing fixed, non-reversible deformities,
thereby avoiding complications that might arise from
such a disabling condition.
Future studies on Pisa syndrome pathogenesis should
explore pathological changes in basal ganglia with a
special focus on asymmetry of neural degeneration,
which has been proposed as a possible mechanism
causing Pisa syndrome, but never fully demonstrated.
There is an absence of both functional MRI and diffusion
tractography studies, which could provide evidence for
both hemispheric asymmetries and alterations in
connections of specific brain structures. Only three
groups of researchers have reported the results of EMG
studies in patients with Pisa syndrome and findings are
inconsistent. These discrepancies might be due to
differences in patient selection criteria or experimental
procedures, especially those related to dynamic or static
assessments and the number of studied muscles.
Establishing a consensus for experimental EMG
procedures might increase understanding of the
physiology of trunk movements in both unaffected and
affected participants. This approach might help to better
understand the crucial issue of possible overlap between
Pisa syndrome and other postural abnormalities in
Parkinson’s disease. Similarly, clinical and functional
comparisons between Pisa syndrome associated with
Parkinson’s disease and atypical parkinsonism and
drug-induced Pisa syndrome could be useful to
understand the pathological mechanisms that predispose
Search strategy and selection criteria
We searched PubMed, Scopus, and ISI Web of Science for
articles published up to May 30, 2016 with the terms “Pisa
syndrome”, “lateral trunk flexion”, “trunk bending”,
“pleurothonus”, “Parkinson’s disease/parkinsonism”, “multiple
system atrophy”, and “progressive supranuclear palsy”.
Selected articles were also obtained from the reference lists of
papers identified by the previous searches. Apart from a few
key studies, only reports published in English were included.
The final reference list was generated on the basis of relevance
to the topics covered in this Review.
www.thelancet.com/neurology Vol 15 September 2016
Review
patients with Parkinson’s disease to the development of
Pisa syndrome and consequent preventive actions.
The present data on interventions for Pisa syndrome
provide only weak evidence for treatment recom-
mendations. Adjustments in drug regimen and the
second-line strategies botulinum toxin injection,
rehabilitation, and surgery might be considered as
treatment options for Pisa syndrome in Parkinson’s
disease, although their efficacy needs to be further
explored in well designed studies involving larger
populations of patients with Parkinson’s disease and in
patients with atypical forms of parkinsonism.
Contributors
All authors contributed equally to this Review.
Declaration of interests
PB reports personal fees from Acorda, personal fees from Union
Chimique Belge, personal fees from Zambon, grants from Abbvie,
grants from Biotie, and grants from Zambon. GS, MTP, MA, and CV
declare no competing interests.
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